JPH09512263A - Method for producing 4,6-dichloropyrimidine - Google Patents
Method for producing 4,6-dichloropyrimidineInfo
- Publication number
- JPH09512263A JPH09512263A JP7527426A JP52742695A JPH09512263A JP H09512263 A JPH09512263 A JP H09512263A JP 7527426 A JP7527426 A JP 7527426A JP 52742695 A JP52742695 A JP 52742695A JP H09512263 A JPH09512263 A JP H09512263A
- Authority
- JP
- Japan
- Prior art keywords
- phosgene
- dihydroxypyrimidine
- mixture
- dichloropyrimidine
- suitable base
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- XJPZKYIHCLDXST-UHFFFAOYSA-N 4,6-dichloropyrimidine Chemical compound ClC1=CC(Cl)=NC=N1 XJPZKYIHCLDXST-UHFFFAOYSA-N 0.000 title claims abstract description 21
- 238000004519 manufacturing process Methods 0.000 title abstract description 6
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 claims abstract description 29
- DUFGYCAXVIUXIP-UHFFFAOYSA-N 4,6-dihydroxypyrimidine Chemical compound OC1=CC(O)=NC=N1 DUFGYCAXVIUXIP-UHFFFAOYSA-N 0.000 claims abstract description 26
- 239000002904 solvent Substances 0.000 claims abstract description 11
- 239000000203 mixture Substances 0.000 claims description 24
- 238000000034 method Methods 0.000 claims description 22
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 8
- JLTDJTHDQAWBAV-UHFFFAOYSA-N N,N-dimethylaniline Chemical group CN(C)C1=CC=CC=C1 JLTDJTHDQAWBAV-UHFFFAOYSA-N 0.000 claims description 8
- 125000000217 alkyl group Chemical group 0.000 claims description 7
- 125000003118 aryl group Chemical group 0.000 claims description 5
- 125000001072 heteroaryl group Chemical group 0.000 claims description 3
- 150000002825 nitriles Chemical class 0.000 claims description 3
- 150000003512 tertiary amines Chemical class 0.000 claims description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 30
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 18
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 12
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 6
- 239000011541 reaction mixture Substances 0.000 description 5
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 239000000284 extract Substances 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 description 3
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 3
- 235000019341 magnesium sulphate Nutrition 0.000 description 3
- 239000012044 organic layer Substances 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- QPFMBZIOSGYJDE-UHFFFAOYSA-N 1,1,2,2-tetrachloroethane Chemical compound ClC(Cl)C(Cl)Cl QPFMBZIOSGYJDE-UHFFFAOYSA-N 0.000 description 2
- BSKHPKMHTQYZBB-UHFFFAOYSA-N 2-methylpyridine Chemical compound CC1=CC=CC=N1 BSKHPKMHTQYZBB-UHFFFAOYSA-N 0.000 description 2
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- FKNQCJSGGFJEIZ-UHFFFAOYSA-N 4-methylpyridine Chemical compound CC1=CC=NC=C1 FKNQCJSGGFJEIZ-UHFFFAOYSA-N 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- CKUAXEQHGKSLHN-UHFFFAOYSA-N [C].[N] Chemical group [C].[N] CKUAXEQHGKSLHN-UHFFFAOYSA-N 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- -1 heterocyclic amines Chemical class 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- TZIHFWKZFHZASV-UHFFFAOYSA-N methyl formate Chemical compound COC=O TZIHFWKZFHZASV-UHFFFAOYSA-N 0.000 description 2
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000012258 stirred mixture Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- AVFZOVWCLRSYKC-UHFFFAOYSA-N 1-methylpyrrolidine Chemical compound CN1CCCC1 AVFZOVWCLRSYKC-UHFFFAOYSA-N 0.000 description 1
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 1
- RMOUBSOVHSONPZ-UHFFFAOYSA-N Isopropyl formate Chemical compound CC(C)OC=O RMOUBSOVHSONPZ-UHFFFAOYSA-N 0.000 description 1
- AHVYPIQETPWLSZ-UHFFFAOYSA-N N-methyl-pyrrolidine Natural products CN1CC=CC1 AHVYPIQETPWLSZ-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 description 1
- 239000003905 agrochemical Substances 0.000 description 1
- 125000005907 alkyl ester group Chemical group 0.000 description 1
- WFDXOXNFNRHQEC-GHRIWEEISA-N azoxystrobin Chemical compound CO\C=C(\C(=O)OC)C1=CC=CC=C1OC1=CC(OC=2C(=CC=CC=2)C#N)=NC=N1 WFDXOXNFNRHQEC-GHRIWEEISA-N 0.000 description 1
- 230000005587 bubbling Effects 0.000 description 1
- KVNRLNFWIYMESJ-UHFFFAOYSA-N butyronitrile Chemical compound CCCC#N KVNRLNFWIYMESJ-UHFFFAOYSA-N 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- SBZXBUIDTXKZTM-UHFFFAOYSA-N diglyme Chemical compound COCCOCCOC SBZXBUIDTXKZTM-UHFFFAOYSA-N 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 239000003880 polar aprotic solvent Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- FVSKHRXBFJPNKK-UHFFFAOYSA-N propionitrile Chemical compound CCC#N FVSKHRXBFJPNKK-UHFFFAOYSA-N 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000002390 rotary evaporation Methods 0.000 description 1
- 150000003839 salts Chemical group 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- YFNKIDBQEZZDLK-UHFFFAOYSA-N triglyme Chemical compound COCCOCCOCCOC YFNKIDBQEZZDLK-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/30—Halogen atoms or nitro radicals
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Plural Heterocyclic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Agricultural Chemicals And Associated Chemicals (AREA)
- Physical Or Chemical Processes And Apparatus (AREA)
Abstract
(57)【要約】 ４，６−ジヒドロキシピリミジンを好適な塩基の存在中において、そして場合により溶媒の存在中において、ホスゲンで処理することを含む４，６−ジクロロピリミジンを製造するための方法。 (57) [Summary] A process for preparing 4,6-dichloropyrimidine comprising treating 4,6-dihydroxypyrimidine with phosgene in the presence of a suitable base and optionally in the presence of a solvent.
Description
【発明の詳細な説明】 ４，６−ジクロロピリミジンの製造方法 本発明は、ホスゲンおよび好適な塩基を用いて４，６−ジヒドロキシピリミジ ン（１）を４，６−ジクロロピリミジン（２）へ転換するための方法に関する。 ４，６−ジクロロピリミジンは農業化学産業において化学中間体として有用であ る。それは特にＩＣＩＡ５５０４の製造において有用である。 例えば、ホスホリルクロライドはジメチルアニリンの存在中で４，６−ジヒド ロキシピリミジンを４，６−ジクロロピリミジンへ転換させるであろうことは知 られている（Journal Chemical Society（1943）574-5、および同書（1951）221 4）。これらの方法に伴う問題は、大規模で使用する場合、かなりの量のリン酸 副生物が産生し、これを何らかの方法で廃棄しなければならないということであ る。 本発明は、４，６−ジヒドロキシピリミジンを好適な塩基の存在中でホスゲン で処理することを含む４，６−ジクロロピリミジンを製造するための方法を提供 する。 ４，６−ジヒドロキシピリミジン（１）は互変異性形（Ａ）および（Ｂ）で存 在することができ、４，６−ジヒドロキシピリミジンへの言及は全てのその互変 異性形を含むものである。 好適な塩基としては、式Ｒ1Ｒ2Ｒ3Ｎ（式中、Ｒ1、Ｒ2およびＲ3は独立してＣ1-10 アルキル、アリール、ヘテロアリールまたはアリール（Ｃ1-4）アルキルで ある）の第３級アミン類、並びにＣ1-10アルキルにより場合により置換された複 素環式アミン類が含まれる。第３級アミン類の例は、トリエチルアミン、４−（ Ｎ，Ｎ−ジメチルアミノ）−ピリジン、Ｎ，Ｎ−ジイソプロピルエチルアミンで あり、特にはジメチルアニリンである。複素環式アミン類の例は、ピリジン、２ −メチルピリジン、４−メチルピリジン、イミダゾールおよびＮ−アルキルピロ リジン（Ｎ−メチルピロリジンなどのような）である。 塩基：ホスゲンのモル比は、１：１０から１０：１の範囲内であり、特には１ ：１から１：４（２：３から２：４．５などのような）の範囲内である。 アルキル基は直鎖または分枝鎖であり、他に断りがない限り、好ましくは１か ら６個、特には１から４個の炭素原子を含有する。例としては、メチル、エチル 、イソプロピル、ｎ−プロピル、ｎ−ブチルおよびtert−ブチルである。 アリールは好ましくはフェニルである。 複素環式アミン類は好ましくは飽和または不飽和の３〜７員炭素窒素環である 。それらは、例えば、ピリジン、イミダゾール、ピロリジンまたはピペリジンで ある。 ヘテロアリールは、３〜７員炭素窒素環である。それは、例えば、ピリジン、 イミダゾール、ピラゾールまたはピロリジンである。 本方法は溶媒または溶媒の混合物中で実施するのが好ましい。塩素化溶媒（例 えば、ジクロロメタン、１，１，２，２−テトラクロロエタンまたはクロロベン ゼン）、エーテル類（例えば、テトラヒドロフラン、グリム（glyme）、ジグリ ム（diglyme）またはトリグリム（triglyme））、極性非プロトン性溶媒［例え ば、エステル類（例えばＣ1-4アルキルエステル、例えばギ酸メチルまたはギ酸 イソプロピル）、またはニトリル類（例えば、プロピオニトリル、ブチロニトリ ル、ベンゾニトリルまたはアセトニトリル）］が好ましい。溶媒の混合物として は、例えば、アセトニトリルおよびジクロロメタンの混合物が挙げられる。 本方法は好ましくは、−１０℃から１３０℃、特には０℃から１２０℃、格別 には１０℃から９０℃の温度範囲で実施される。 一つの側面において、本発明は、ホスゲンを４，６−ジヒドロキシピリミジン および好適な塩基の混合物に添加することを含む４，６−ジクロロピリミジンを 製造するための方法を提供する。 さらに別の側面において、本発明は、ホスゲンを４，６−ジヒドロキシピリミ ジンおよび好適な塩基の混合物に添加することを含む４，６−ジクロロピリミジ ンを製造するための方法において、当該方法において使用すべき全てのホスゲン を当該方法の最初に添加することを特徴とする方法を提供する。 さらに別の側面において、本発明は、ホスゲンを塩素化溶媒中の４，６−ジヒ ドロキシピリミジンおよび好適な塩基（例えばジメチルアニリンまたはジイソプ ロピルエチルアミン）の混合物に添加することを含む４，６−ジクロロピリミジ ンを製造するための方法において、４，６−ジヒドロキシピリミジン：好適な塩 基：ホスゲンのモル比が１：（０．８から２．５）：（２．５から３．６）の範 囲内、特には１：（１．５から２．２）：（２．９から３．３）の範囲内である ことを特徴とする方法を提供する。 さらに別の側面において本発明は、ホスゲンをニトリル溶媒中の４，６−ジヒ ドロキシピリミジンおよび好適な塩基（例えばジメチルアニリンまたはジイソプ ロピルエチルアミン）の混合物に添加することを含む４，６−ジクロロピリミジ ンを製造するための方法において、４，６−ジヒドロキシピリミジン：好適な塩 基：ホスゲンのモル比が１：（０．１から２．４）：（４から９）の範囲内、特 には１：（０．１から２．１）：（４．４から６．５）の範囲内であることを特 徴とする方法を提供する。 さらに別の側面において本発明は、４，６−ジクロロピリミジンを製造するた めの方法において、当該方法が、ホスゲンを好適な溶媒（例えばジクロロメタン 、アセトニトリルまたはテトラヒドロフラン）中の４，６−ジヒドロキシピリミ ジンおよび好適な塩基（例えばジメチルアニリン）の混合物に添加することを含 み、当該方法において使用すべき全てのホスゲンを当該方法の最初に添加し、そ して反応混合物を（好ましくは１から３０時間、特には１から６時間または１５ から２４時間）加熱することを含むことを特徴とする方法を提供する。好適な塩 基は、生成物単離の間に（塩の形態において）回収することができ、再利用する ことができる。 以下の実施例により本発明を例示する。以下の実施例で使用した装置は、使用 前に乾燥し、そして反応は無水条件を使用して窒素下で実施した。 実施例１ ４，６−ジヒドロキシピリミジン（０．９４ｇ）をジクロロメタン中に懸濁し 、ジメチルアニリン（１，１２ｇ）を添加し、ホスゲン（５ｇ）を次いで混合物 中に凝縮した。得られた混合物を２４時間環流加熱し、次いで冷却し、水中に注 いだ。得られた有機層の高圧液体クロマトグラフィー（ｈｐｌｃ）分析により、 ４， ６−ジヒドロキシピリミジン：４，６−ジクロロピリミジンの比率が３９：５８ であることが示された。 実施例２ ４，６−ジヒドロキシピリミジン（２０．５ｇ）をジクロロメタン（４００ｍ ｌ）中に攪拌しながら分散した。ジメチルアニリン（４０．４ｇ）を攪拌した混 合物に添加し、その系を密封した（スクラッバーへの出口線を除いて）。ホスゲ ンガス（５６ｇ）をシリンダーから導入し、冷却フィンガー上に凝縮し、圧力均 等化滴下漏斗中に回収した。回収後、ホスゲン液体を反応混合物に１５分間かけ て添加した。混合物を加熱し、環流で（約２９℃）１７時間攪拌し、その後、混 合物を室温まで冷却し、過剰のホスゲンを窒素と共に散布（sparging）すること によって除去した。 冷却して周囲温度を維持しながら水（４００ｍｌ）を攪拌反応物に徐々に添加 した。有機層を分離し、次いで水層をジクロロメタン（２×１００ｍｌ）で抽出 した。合わせた抽出物を無水硫酸ナトリウム上で乾燥し、回転式エバポレーショ ンによって濃縮し、４，６−ジクロロピリミジンを、８０％（ｈｐｌｃ分析）の 収率に等しい橙色の結晶固体（２７ｇ）として得た。 実施例３ ４，６−ジヒドロキシピリミジン（２．０ｇ）をアセトニトリル（４０ｍｌ） 中に攪拌しながら分散し、ジメチルアニリン（２．１ｇ）を添加し、混合物を５ ０℃に加熱した。ホスゲンガス（１４．６ｇ）を（それを混合物を通して泡立た せることによって）混合物に１時間かけて添加した。混合物を５０℃で４．５時 間維持し、室温に冷却し、過剰のホスゲンを窒素と共に散布することによって除 去した。得られた反応物の分析（ｈｐｌｃ）はそれが４，６−ジクロロピリミジ ン（８１％の収率）を含むことを示した。 実施例４ アセトニトリル（１００ｍｌ）中の４，６−ジヒドロキシピリミジン（５．１ ４ｇ、１当量）およびイミダゾール（６．１９ｇ、２当量）の混合物にホスゲン （２８ｇ、６．２当量）を添加した。得られた混合物を室温で２と１／４時間、 そして５０℃で１時間攪拌した。反応混合物を一晩窒素で洗浄し、次いで、水お よびジクロロメタンの間で分画した。有機層を分離し、水層をジクロロメタンで さらに２回抽出した。有機抽出物を合わせて、水で洗浄し（２回）、硫酸マグネ シウム上で乾燥し、蒸発乾燥し、淡黄色の固体として４，６−ジクロロピリミジ ンが得られた。 実施例５ アセトニトリル（１００ｍｌ）中の４，６−ジヒドロキシピリミジン（５．１ ８ｇ、１当量）および４−（Ｎ，Ｎ−ジメチルアミノ）ピリジン（０．５５ｇ、 ０．１当量）の攪拌混合物に、ホスゲン（２８ｇ、１９．７ｍｌ、６．２当量） を２アリコートで添加した。得られた混合物を室温で１０分間攪拌し、次いで、 ５５℃で４時間攪拌した。反応混合物を空気で洗浄し、その後、水（２００ｍｌ ）を添加した。得られた混合物をジクロロメタン（３×１００ｍｌ）で抽出した 。有機抽出物を合わせて、水（１００ｍｌ）で洗浄し、硫酸マグネシウム上で乾 燥し、蒸発乾燥して４，６−ジクロロピリミジン（４．６３ｇ）が得られた。 実施例６ アセトニトリル（１００ｍｌ）中の４，６−ジヒドロキシピリミジン（５．１ ８ｇ、１当量）およびＮ，Ｎ−ジイソプロピルエチルアミン（１１．７５ｇ、２ 当量）の攪拌混合物に、ホスゲン（２８ｇ、１９．７ｍｌ、６．２当量）を２ア リコートで添加した。得られた混合物を室温で１０分間攪拌し、次いで、５５℃ で４時間攪拌した。反応混合物を空気と共に一晩散布し、その後、水（１００ｍ ｌ）を添加した。得られた混合物をジクロロメタン（３×１００ｍｌ）で抽出し た。有機抽出物を合わせて、水（１００ｍｌ）で洗浄し、硫酸マグネシウム上で 乾燥し、蒸発乾燥して４，６−ジクロロピリミジン（６．３５ｇ）が得られた。 DETAILED DESCRIPTION OF THE INVENTION Process for Producing 4,6-Dichloropyrimidine The present invention converts 4,6-dihydroxypyrimidine (1) to 4,6-dichloropyrimidine (2) using phosgene and a suitable base. For how to. 4,6-Dichloropyrimidine is useful as a chemical intermediate in the agrochemical industry. It is particularly useful in the manufacture of ICIA5504. For example, phosphoryl chloride is known to convert 4,6-dihydroxypyrimidine to 4,6-dichloropyrimidine in the presence of dimethylaniline (Journal Chemical Society (1943) 574-5, and ibid. 1951) 221 4). The problem with these methods is that when used on a large scale, a significant amount of phosphate by-product is produced which must be discarded in some way. The present invention provides a process for preparing 4,6-dichloropyrimidine which comprises treating 4,6-dihydroxypyrimidine with phosgene in the presence of a suitable base. 4,6-Dihydroxypyrimidine (1) can exist in tautomeric forms (A) and (B), references to 4,6-dihydroxypyrimidine include all tautomeric forms thereof. Suitable bases include those of the formula R 1 R 2 R 3 N where R 1 , R 2 and R 3 are independently C 1-10 alkyl, aryl, heteroaryl or aryl (C 1-4 ) alkyl. ) Of tertiary amines as well as heterocyclic amines optionally substituted with C 1-10 alkyl. Examples of tertiary amines are triethylamine, 4- (N, N-dimethylamino) -pyridine, N, N-diisopropylethylamine, especially dimethylaniline. Examples of heterocyclic amines are pyridine, 2-methylpyridine, 4-methylpyridine, imidazole and N-alkylpyrrolidines (such as N-methylpyrrolidine and the like). The base: phosgene molar ratio is in the range 1:10 to 10: 1, especially in the range 1: 1 to 1: 4 (such as 2: 3 to 2: 4.5). . Alkyl groups are straight-chain or branched and preferably contain 1 to 6, in particular 1 to 4 carbon atoms, unless otherwise stated. Examples are methyl, ethyl, isopropyl, n-propyl, n-butyl and tert-butyl. Aryl is preferably phenyl. Heterocyclic amines are preferably saturated or unsaturated 3 to 7 membered carbon nitrogen rings. They are, for example, pyridine, imidazole, pyrrolidine or piperidine. Heteroaryl is a 3-7 membered carbon nitrogen ring. It is, for example, pyridine, imidazole, pyrazole or pyrrolidine. The method is preferably carried out in a solvent or a mixture of solvents. Chlorinated solvents (eg dichloromethane, 1,1,2,2-tetrachloroethane or chlorobenzene), ethers (eg tetrahydrofuran, glyme, diglyme or triglyme), polar aprotic solvents [For example, esters (for example, C 1-4 alkyl ester such as methyl formate or isopropyl formate), or nitriles (for example, propionitrile, butyronitrile, benzonitrile or acetonitrile)] are preferable. Examples of the solvent mixture include a mixture of acetonitrile and dichloromethane. The process is preferably carried out in the temperature range from -10 ° C to 130 ° C, in particular 0 ° C to 120 ° C, especially 10 ° C to 90 ° C. In one aspect, the invention provides a method for making 4,6-dichloropyrimidine comprising adding phosgene to a mixture of 4,6-dihydroxypyrimidine and a suitable base. In yet another aspect, the invention is a method for producing 4,6-dichloropyrimidine comprising adding phosgene to a mixture of 4,6-dihydroxypyrimidine and a suitable base, which method should be used in the method. A method is provided, characterized in that all phosgene is added at the beginning of the method. In yet another aspect, the present invention provides 4,6-dichloropyrimidine which comprises adding phosgene to a mixture of 4,6-dihydroxypyrimidine and a suitable base (eg, dimethylaniline or diisopropylethylamine) in a chlorinated solvent. In the process for the preparation, the molar ratio of 4,6-dihydroxypyrimidine: suitable base: phosgene is in the range 1: (0.8 to 2.5) :( 2.5 to 3.6), especially A method is provided which is in the range of 1: (1.5 to 2.2) :( 2.9 to 3.3). In yet another aspect, the present invention prepares 4,6-dichloropyrimidine which comprises adding phosgene to a mixture of 4,6-dihydroxypyrimidine and a suitable base (eg dimethylaniline or diisopropylethylamine) in a nitrile solvent. The molar ratio of 4,6-dihydroxypyrimidine: suitable base: phosgene is in the range 1: (0.1 to 2.4) :( 4 to 9), in particular 1: (0.1 To 2.1): within the range of (4.4 to 6.5). In yet another aspect, the present invention provides a method for producing 4,6-dichloropyrimidine, which comprises phosgene in a suitable solvent (eg, dichloromethane, acetonitrile or tetrahydrofuran) and All the phosgene to be used in the process is added at the beginning of the process, and the reaction mixture is added (preferably from 1 to 30 hours, especially from 1 to 30). Heating for 6 hours or 15 to 24 hours). The suitable base can be recovered (in salt form) during product isolation and reused. The following examples illustrate the invention. The equipment used in the following examples was dried before use and the reaction was carried out under nitrogen using anhydrous conditions. Example 1 4,6-Dihydroxypyrimidine (0.94 g) was suspended in dichloromethane, dimethylaniline (1,12 g) was added and phosgene (5 g) was then condensed into the mixture. The resulting mixture was heated at reflux for 24 hours, then cooled and poured into water. High pressure liquid chromatography (hplc) analysis of the resulting organic layer showed that the ratio of 4,6-dihydroxypyrimidine: 4,6-dichloropyrimidine was 39:58. Example 2 4,6-Dihydroxypyrimidine (20.5 g) was dispersed in dichloromethane (400 ml) with stirring. Dimethylaniline (40.4 g) was added to the stirred mixture and the system was sealed (except for the exit line to the scrubber). Phosgene gas (56 g) was introduced from the cylinder, condensed on the cooling fingers and collected in a pressure equalizing dropping funnel. After recovery, phosgene liquid was added to the reaction mixture over 15 minutes. The mixture was heated and stirred at reflux (about 29 ° C.) for 17 hours, after which the mixture was cooled to room temperature and excess phosgene was removed by sparging with nitrogen. Water (400 ml) was added slowly to the stirred reaction while cooling and maintaining ambient temperature. The organic layer was separated, then the aqueous layer was extracted with dichloromethane (2 x 100 ml). The combined extracts were dried over anhydrous sodium sulphate and concentrated by rotary evaporation to give 4,6-dichloropyrimidine as an orange crystalline solid (27g) with an yield of 80% (hplc analysis). . Example 3 4,6-Dihydroxypyrimidine (2.0 g) was dispersed in acetonitrile (40 ml) with stirring, dimethylaniline (2.1 g) was added, and the mixture was heated to 50 ° C. Phosgene gas (14.6 g) was added to the mixture (by bubbling it through the mixture) over 1 hour. The mixture was maintained at 50 ° C. for 4.5 hours, cooled to room temperature and excess phosgene was removed by sparging with nitrogen. Analysis of the resulting reaction (hplc) showed that it contained 4,6-dichloropyrimidine (81% yield). Example 4 Phosgene (28 g, 6.2 eq) was added to a mixture of 4,6-dihydroxypyrimidine (5.14 g, 1 eq) and imidazole (6.19 g, 2 eq) in acetonitrile (100 ml). The resulting mixture was stirred at room temperature for 2 and 1/4 hours and at 50 ° C. for 1 hour. The reaction mixture was flushed with nitrogen overnight and then partitioned between water and dichloromethane. The organic layer was separated and the aqueous layer was extracted twice more with dichloromethane. The combined organic extracts were washed with water (twice), dried over magnesium sulphate and evaporated to dryness to give 4,6-dichloropyrimidine as a pale yellow solid. Example 5 To a stirred mixture of 4,6-dihydroxypyrimidine (5.18 g, 1 eq) and 4- (N, N-dimethylamino) pyridine (0.55 g, 0.1 eq) in acetonitrile (100 ml). , Phosgene (28 g, 19.7 ml, 6.2 eq) was added in two aliquots. The resulting mixture was stirred at room temperature for 10 minutes, then at 55 ° C. for 4 hours. The reaction mixture was washed with air and then water (200 ml) was added. The resulting mixture was extracted with dichloromethane (3 x 100 ml). The combined organic extracts were washed with water (100 ml), dried over magnesium sulphate and evaporated to dryness to give 4,6-dichloropyrimidine (4.63 g). Example 6 Phosgene (28 g, 19. 7 ml, 6.2 eq) was added in 2 aliquots. The resulting mixture was stirred at room temperature for 10 minutes and then at 55 ° C. for 4 hours. The reaction mixture was sparged with air overnight, after which water (100 ml) was added. The resulting mixture was extracted with dichloromethane (3 x 100 ml). The combined organic extracts were washed with water (100 ml), dried over magnesium sulphate and evaporated to dryness to give 4,6-dichloropyrimidine (6.35 g).
───────────────────────────────────────────────────── フロントページの続き (72)発明者 ジョーンズ，ジョン・デイヴィッド イギリス国ランカシャー ビーエル８ ４ イーディー，ベリー，グリーンマウント, キーツ・ロード 57────────────────────────────────────────────────── ─── Continuation of front page (72) Inventor Jones, John David Lancashire UK 8 Edie, Berry, Green Mount, Keats Road 57
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| Application Number | Priority Date | Filing Date | Title |
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| GB9408270.8 | 1994-04-26 | ||
| GB9408270A GB9408270D0 (en) | 1994-04-26 | 1994-04-26 | Chemical process |
| PCT/GB1995/000676 WO1995029166A1 (en) | 1994-04-26 | 1995-03-27 | Process for the preparation of 4,6-dichloropyrimidine |
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| US (1) | US5750694A (en) |
| EP (2) | EP1273574B1 (en) |
| JP (1) | JP3688295B2 (en) |
| CN (2) | CN1255388C (en) |
| AT (2) | ATE240301T1 (en) |
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| CZ (1) | CZ289265B6 (en) |
| DE (2) | DE69530765T2 (en) |
| DK (2) | DK0757678T3 (en) |
| ES (2) | ES2199983T3 (en) |
| GB (1) | GB9408270D0 (en) |
| HU (1) | HU220374B (en) |
| IL (1) | IL113143A (en) |
| PL (1) | PL182718B1 (en) |
| RO (1) | RO117450B1 (en) |
| RU (1) | RU2156240C2 (en) |
| SK (1) | SK137196A3 (en) |
| TW (1) | TW388759B (en) |
| WO (1) | WO1995029166A1 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2005529184A (en) * | 2002-06-13 | 2005-09-29 | バイエル・クロツプサイエンス・アクチエンゲゼルシヤフト | Process for the preparation of 4,6-dichloro-5-fluoropyrimidine |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AT402818B (en) * | 1995-06-02 | 1997-09-25 | Chemie Linz Gmbh | METHOD FOR PRODUCING PURE 4,6-DICHLORPYRIMIDINE |
| DE19531299A1 (en) * | 1995-08-25 | 1997-02-27 | Bayer Ag | Process for the preparation of 4,6-dichloropyrimidines |
| US6160117A (en) * | 1997-11-06 | 2000-12-12 | Zeneca Limited | Chemical process |
| WO2000046212A1 (en) * | 1999-02-05 | 2000-08-10 | Syngenta Participations Ag | Method of producing substituted pyrimidine derivatives |
| DE19929353A1 (en) | 1999-06-26 | 2000-12-28 | Bayer Ag | Preparation of 4,6-dichloropyrimidine used as plant protection agent intermediates comprises reacting 4-chloro-6-methoxypyrimidine with acid chloride |
| DE19929350A1 (en) * | 1999-06-26 | 2000-12-28 | Bayer Ag | Preparation of 4,6-dichloropyrimidine used as plant protection agent intermediates comprises reacting 4-chloro-6-methoxypyrimidine with acid chloride and halogen hydride |
| DE19935322A1 (en) | 1999-07-28 | 2001-02-01 | Bayer Ag | Process for the preparation of 4,6-dichloropyrimidine with phosgene |
| DE19938500A1 (en) | 1999-08-13 | 2001-02-15 | Bayer Ag | Process for the preparation of 4,6-dichloropyrimidine with sulfur and phosphorus compounds |
| US20020042514A1 (en) * | 2000-06-26 | 2002-04-11 | Doyle Timothy John | Synthesis of chlorinated pyrimidines |
| US6608199B2 (en) | 2000-07-07 | 2003-08-19 | Syngenta Limited | Synthesis of chlorinated pyrimidines |
| US6982331B2 (en) * | 2001-06-08 | 2006-01-03 | Syngenta Crop Protection, Inc. | Synthesis of chlorinated pyrimidines |
| CN1321986C (en) * | 2005-06-20 | 2007-06-20 | 江苏省激素研究所有限公司 | Method for preparing 4,6 dichloropyridine |
| US10018782B2 (en) | 2015-05-28 | 2018-07-10 | Corning Optical Communications LLC | Optical fiber stripping methods and apparatus |
| CN105906570A (en) * | 2016-05-13 | 2016-08-31 | 安徽广信农化股份有限公司 | Synthesis technology of 4,6-dichloropyrimidine |
| CN105859637A (en) * | 2016-05-13 | 2016-08-17 | 安徽广信农化股份有限公司 | Synthesis of 4,6-dichloropyrimidine and process optimization |
| CN105859636A (en) * | 2016-05-13 | 2016-08-17 | 安徽广信农化股份有限公司 | Synthesis method of 4,6-dichloropyrimidine with 4,6-dihydroxypyrimidine serving as midbody |
| CN106187913A (en) * | 2016-07-19 | 2016-12-07 | 安徽广信农化股份有限公司 | A kind of production technology of 4,6 dichloro pyrimidines after improvement |
| CN106045917A (en) * | 2016-07-19 | 2016-10-26 | 安徽广信农化股份有限公司 | Synthetic process for preparing 4,6-dichloropyrimidine through one-step method |
| CN108178748B (en) * | 2018-01-19 | 2021-04-06 | 和记黄埔医药（上海）有限公司 | The synthetic method of 4,6-dichloropyrimidine-5-carbonitrile |
| CN109516958B (en) * | 2018-12-26 | 2020-12-08 | 杭州布朗生物医药科技有限公司 | Preparation method of 2, 4-dichloropyrimidine and derivatives thereof |
| CN116924996A (en) * | 2023-07-14 | 2023-10-24 | 江苏剑牌农化股份有限公司 | A kind of synthesis technology of dichloropyrimidine |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR1310810A (en) * | 1960-11-26 | 1962-11-30 | Basf Ag | Process for the production of heterocyclic chlorine compounds |
| DE3220105A1 (en) * | 1982-05-28 | 1983-12-01 | Bayer Ag, 5090 Leverkusen | METHOD FOR THE PRODUCTION IN (ALPHA) POSITION CHLORINATED NITROGEN HETEROCYCLES |
| DE3228712A1 (en) * | 1982-07-31 | 1984-02-02 | Bayer Ag, 5090 Leverkusen | METHOD FOR PRODUCING 2,4,5,6-TETRACHLORPYRIMIDINE |
| DE3431698A1 (en) * | 1984-08-29 | 1986-03-13 | Bayer Ag, 5090 Leverkusen | 5,5-DICHLOR-4,5-DIHYDRO-6-HYDROXY-2-TRICHLORMETHYL-PYRIMIDIN-4-ON, A METHOD FOR THE PRODUCTION THEREOF AND ITS USE |
| DE3441789A1 (en) * | 1984-11-15 | 1986-05-15 | Bayer Ag, 5090 Leverkusen | 5,6-DICHLOR-4-HYDROXY-2-TRICHLORMETHYLPYRIMIDINE |
| DE3441935A1 (en) * | 1984-11-16 | 1986-05-28 | Bayer Ag, 5090 Leverkusen | METHOD FOR PRODUCING 2,4-DIHYDROXYPYRIMIDINES |
| GB8916698D0 (en) * | 1989-07-21 | 1989-09-06 | Beecham Group Plc | Novel process |
| DE4222518A1 (en) * | 1992-07-09 | 1994-01-13 | Bayer Ag | Process for the production of 5- (trifluoromethyl) uracil and the new compounds 2,4-dichloro-5-trichloromethyl-pyrimidine and 2,4-difluoro-5-trifluoromethyl-pyrimidine |
| GB9220585D0 (en) * | 1992-09-30 | 1992-11-11 | Smithkline Beecham Plc | Pharmaceuticals |
| CN1082031A (en) * | 1993-05-20 | 1994-02-16 | 郑州市孝义制药厂 | The preparation method of sulfamonomethoxine |
| DE4408404A1 (en) * | 1994-03-12 | 1995-09-14 | Huels Chemische Werke Ag | Process for the preparation of chloropyrimidines |
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1994
- 1994-04-26 GB GB9408270A patent/GB9408270D0/en active Pending
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1995
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- 1995-03-27 AT AT02022777T patent/ATE308526T1/en active
- 1995-03-27 BR BR9507481A patent/BR9507481A/en not_active Application Discontinuation
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- 1995-03-27 EP EP02022777A patent/EP1273574B1/en not_active Expired - Lifetime
- 1995-03-27 HU HU9602912A patent/HU220374B/en unknown
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- 1995-03-27 IL IL11314395A patent/IL113143A/en not_active IP Right Cessation
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- 1995-03-27 DK DK02022777T patent/DK1273574T3/en active
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2005529184A (en) * | 2002-06-13 | 2005-09-29 | バイエル・クロツプサイエンス・アクチエンゲゼルシヤフト | Process for the preparation of 4,6-dichloro-5-fluoropyrimidine |
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